Chiral amino-methyl ferrocene derivatives

ABSTRACT

A ferrocene derivatives represented by the following formula (I): ##STR1## can be a useful ligand to metals with Lewis acidity and is used as a catalyst for asymmetric synthesis with good enantioselectivety. This ferrocene derivatives is synthesized from a novel haloferrocene derivative represented by formula (II) and the haloferrocene derivative is synthesized from a novel ferrocene derivative represented by formula (III).

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a novel ferrocene derivative and, more in detail, an optically active ferrocene derivative as a useful catalyst for asymmetric synthesis. Further, the present invention relates to an optically active haloferrocene and ferrocene derivative.

2. Description of Prior Art

A catalyst is often used for an asymmetric synthesis method which is one of processes for preparation of an optically active substance. Examples of well known catalysts include ephedrine and prolinol derivatives which are derived from natural sources.

Derivatives from natural sources, however, have specificity to a substrate and as a result, some substrates exhibit good enantioselectivity but the other substrates do not. Therefore, these derivatives from natural sources can not be applied to or are not suitable to many reactions.

In these circumstances, some improvement in catalysts for asymmetric synthesis derived from natural sources were attempted in order to reduce the above-mentioned specificity to a substrate and improve properties such as reaction efficiency. However, in some cases, it is not easy to change a substituent on an asymmetric carbon in the catalyst and it is impossible to obtain a catalyst with desirable properties.

Ferrocenylphosphine, one of known optically active ferrocene derivatives, is used as a chiral ligand to transition metals such as palladium and rhodium. Transition metals with ferrocenylphosphine as the ligand are used as catalysts for asymmetric synthesis. (See T. Hayashi et al., Bull. Chem. Soc. Jpn., Vol.53, 1138 (1980); Tetrahedron Lett., 1979, 2155; J. Org. Chem., Vol. 53, 113 (1988).) However, this catalyst can be applied only to reactions in which transition metals such as palladium and rhodium work as a catalyst, and is not applicable to a wide range of reaction.

Further, it is known that catalysts using metals with Lewis acidity such as zinc, boron, aluminum, titanium, cerium and nickel exhibit good enantioselectivity in asymmetric induction. However, no catalyst consisting of a metal with Lewis acidity to which ferrocenylphosphine is coordinated has afforded high enantioselectivity.

A provision of an optically active ferrocene derivative coordinating to a metal with Lewis acidity and exhibiting good enantioselectivity is desired.

Furthermore, aside from a metal coordination catalyst, a polymer comprising an optically active ferrocene derivative is also aspired to be provided. The polymer comprising an optically active ferrocene derivative will be used as a catalyst for heterogeneous asymmetric synthesis and a gel for an optical resolution.

An object of the present invention is to provide a novel catalyst for asymmetric synthesis which can be used instead of the above-mentioned compounds derived from natural sources.

A further object of the present invention is to provide a catalyst for asymmetric synthesis of which substituents on the asymmetric carbon are easily exchangeable.

An another object of the present invention is to provide an optically active ferrocene derivative which can be a ligand to a metal with Lewis acidity.

A further object of the present invention is to provide an optically active ferrocene derivative usable as a starting material of an optically active polymer.

SUMMARY OF THE INVENTION

The present invention relates to a ferrocene derivative with chirality represented by the formula (I): ##STR2## In the formula (I), R¹ represents an alkyl group, preferably a lower alkyl group having 1 to 6 carbon atoms. R² and R³ are the same or different and represent an alkyl group, preferably a lower alkyl group having 1 to 6 carbon atoms, an aryl group, preferably a phenyl group or a benzyl group, or R² and R³ form a heterocyclic ring, preferably a heterocyclic ring having 4 to 6 carbon atoms, together with a nitrogen atom to which R² and R² bond. R⁴ and R⁵ are the same or different and represent hydrogen, a lower alkyl group having 2 to 6 carbon atoms, an aryl group, an anthracenyl group or a ferrocenyl group, or R⁴ and R⁵ form a cycloalkyl group having 5 to 7 carbon atoms or a anthracenyl group together with a carbon atom to which R⁴ and R⁵ bond. It is provided that R⁴ and R.sup. 5 are not hydrogen simultaneously, and when R¹, R² and R³, are methyl groups, R⁴ and R⁵ are not phenyl groups simultaneously and are not respectively p-methoxyphenyl and hydrogen.

DETAILED DESCRIPTION OF THE INVENTION

Examples of a lower alkyl group having 1 to 6 carbon atoms represented by R¹, R² and R³ in formula (I) include methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl and n-hexyl. Particulary, methyl and iso-propyl are preferred as R¹, and methyl, ethyl and iso-propyl are preferred as R², and R³. Further examples of a heterocyclic ring which is formed with R² and R³ together with a nitrogen atom to which R² and R³ bond include pyrrolidine and piperidine, preferably piperidine.

Examples of a lower alkyl group having 2 to 6 carbon atoms represented by R⁴ and R⁵ include ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl and n-hexyl, preferably iso-propyl and tert-butyl. Examples of an aryl group represented by R⁴ and R⁵ include phenyl, o-tolyl, p-tolyl, mesityl, 2,6-dimethoxyphenyl and p-chlorophenyl. Further, examples of a cycloalkyl group which is formed with R⁴ and R⁵ together with a carbon atom to which R⁴ and R⁵ bond include cyclopentyl, cyclohexyl and cycloheptyl, preferably cyclohexyl.

Examples of the compounds of the present invention represented by formula (I) are shown in Table 1 below.

                  TABLE 1                                                          ______________________________________                                         No.  R.sup.1 R.sup.2  R.sup.3                                                                              R.sup.4   R.sup.5                                  ______________________________________                                         1    Me                                                                                      ##STR3##    Ph        Ph                                         2    Me      Me       Me    iso-Pr    iso-Pr                                   3    Me      Me       Me                                                                                    ##STR4##                                          4    Me      Et       Et    Ph        Ph                                       5    Me                                                                                      ##STR5##                                                                                    ##STR6##                                            6    Me      iso-Pr   iso-Pr                                                                               Ph        Ph                                       7    Me      Me       Me    Ph        H                                        8    Me      Me       Me    t-Bu      H                                        9    Me                                                                                      ##STR7##    t-Bu      H                                          ______________________________________                                          Me: methyl, Et: ethyl, isoPr: isopropyl, tBu: tertbutyl, Ph: phenyl            "C" in the column of R.sup.4 and R.sup.5 of No. 3 and No. 5 represents a       carbon atom to which R.sup.4 and R.sup.5 bond.                           

Further, the present invention relates to a haloferrocene derivative represented by formula (II) and a forrocene derivative represented by formula (III): ##STR8##

In formulas (II) and (III), R⁶ represents hydrogen, an alkyl group, a benzyl group or an aryl group, R⁷ and R⁸ represent respectively hydrogen, an alkyl group, a benzyl group, an aryl group, or unsubstituted or substituted 2-hydroxyethyl group, or R⁷ and R⁸ can be form a heterocyclic ring together with a nitrogen atom. One of X¹ and X² is hydrogen and the other is halogen.

In formulas (II) and (III), an alkyl group is preferably an alkyl group having 1 to 6 carbon atoms and is exemplified by methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl and n-pentyl. Examples of an aryl group include phenyl, p-tolyl, o-tolyl, p-methoxyphenyl, p-chlorophenyl, o-chlorophenyl and p-nitrophenyl. Examples of substituents of 2-hydroxyethyl group include methyl, ethyl, iso-propyl, tert-butyl, phenyl and p-tolyl Examples of 2-hydroxyethyl group include 2-hydroxyethyl, (R)-2-hydroxypropyl, (S)-2-hydroxypropyl, (1S,2R)-1-methyl-2-phenyl-2-hydroxyethyl, (1R, 2S)-1-methyl-2-phenyl 2-hydroxyethyl, (R)-2-phenyl-2-hydroxyethyl, (S)-2-phenyl-2-hydroxyethyl, (S)-2-t-butyl-2-hydroxyethyl.

Further, examples of a heterocyclic ring which is formed with R⁷ and R⁸ together with a nitrogen atom to which R⁷ and R⁸ bond (-NR⁷ R⁸) include pyrrolidyl, (S)-2-hydroxymethylpyrrolidyl, (R)-2-hydroxymethylpyrrolidyl, piperidyl, morpholyl, (S)-2-(diphenylhydroxymethyl) pyrrolidyl, (S)-2-[(S)-phenylhydroxymethyl]pyrrolidyl, (S)-2-[(R)-phenylhydroxymethyl]pyrrolidyl.

Further, examples of halogen group include chloro, bromo and iodo.

It is preferred that the haloferrocene derivative represented by formula (II) exhibits optical activity. Examples of the haloferrocene are listed below:

(R)-N,N-dimethyl-1-[(S)-2-iodoferrocenyl]ethylamine,

(S)-N,N-dimethyl-l-[(R)-2-iodoferrocenyl]ethylamine,

N-[(R)-1-((S)-2-iodoferrocenyl)ethyl]N methylethanolamine,

N-[(R)-1-((S)-2-iodoferrocenyl)ethyl]-(S)-prolinol,

N-[(S)-1-((R)-2-iodoferrocenyl)ethyl]-(S)-prolinol,

N-[(R)-1-((S)-2-iodoferrocenyl)ethyl]-(1S,2R)-ephedrine,

N-[(S)-1-((R)-2-iodoferrocenyl)ethyl]-(1S,2R)-ephedrine,

N-[(R)-1-((S)-2-iodoferrocenyl)ethyl]-(1R,2S)-ephedrine,

N-[(R)-1-((S)-2-iodoferrocenyl)ethyl]-(1S,2R)-norephedrine,

N-[(R)-1-((S)-2-iodoferrocenyl)ethyl]-N-t-butyl-(S)-2-phenylethanolamine,

N-[(S)-1-((R)-2-iodoferrocenyl)ethyl]-N-t-butyl-(S)-2-phenylethanolamine,

N-[(R)-1-((S)-2-iodoferrocenyl)ethyl]-N-t-butyl-(S)-1-phenylethanolamine,

(R)-N,N-dimethyl-1-[(S)-2-bromoferrocenyl]ethylamine,

N-[(R)-1-((S)-2-bromoferrocenyl)ethyl]-(1S,2R)-ephedrine,

N-(2-iodoferrocenyl)methyl-(1S,2R)-ephedrine.

A process for preparation of the derivative represented by formula (II) will be explained below:

(A) process 1:

The haloferrocene derivative represented by formula (II) is obtained by reacting a ferrocene derivative represented by formula (III): ##STR9## (In the formula, definition of R⁴, R⁷ and R⁸ are the same as those above.) with organic lithium compound to obtain a lithiated compound and then reacting the resulting lithiated compound with halogenation agent.

Examples of the organic lithium compound used for the lithiation include n-butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium and phenyl lithium. An amount of the lithium compound suitably ranges from 0.1 to 2.0 equivalents, preferably from 0.7 to 1.5 equivalents to the ferrocene derivative (III). It is preferred to use these lithium compound in the form of 5 to 30% hexane or ether solution. Further, it is suitable that the lithiation reaction is conducted in the presence of one or more solvent(s), for example ethers such as ethylether and tetrahydrofurane); straight chain hydrocarbons such as pentane, hexane and heptane; or aromatic hydrocarbons such as benzene, toluene, xylene and dichlorobenzene under the following conditions:

Reaction temperature:-30° to 50° C., preferably -10° to 30° C.

Reaction time: 0.1 to 5 hours

Reaction pressure: atmospheric pressure to increased pressure, preferably from 1 to 3 atms

Atmosphere: nitrogen or argon

The lithiation reaction can also be carried out in accordance with the method reported by Ugi et al. J. Am. Chem Soc., Vol. 92, 5389 (1970).

The halogenation of the lithiation compound is conducted by using a halogenation agent such as iodine, bromine, chlorine, N-iodosuccinimide, N-chlorosuccinimide. The halogenation agent can be added to a reaction mixture as it is or a solution dissolving it in a solvent.

The solvents exemplified as those used for lithiation reaction can be used as the solvent for the halogenation agent and halogenation reation. An amount of halogenation agent suitably ranges from 0.1 to 2.0 equivalents, preferably from 0.7 to 1.5 equivalents to the ferrocene derivative (III) used in the lithiation reation. It is preferred to conduct the halogenation reaction under the following conditions:

Reaction temperature: -120° to 0° C., preferably -100° to -30° C.

Reaction time: 0.1 to 10 hours

Reaction pressure: atmospheric pressure to increased pressure, preferably from 1 to 3 atms

Atmosphere: nitrogen or argon

The progress of the halogenation reaction can be analyzed by thin layer chromatography. At the end of the reaction, the reaction is stopped by addition of water to the reaction system and then the reaction mixture is subjected to extraction with ether. Then the objective compound is collected from the extract solution by column chromatography.

Some of the ferrocene derivatives (III) used as the starting material in the above process 1 are known. (Refer to I. Ugi et al., J. Org. Chem., vol.37, 3052 (1972); Liebigs Ann. Chem., 1986, 251; S. Allenmark et al., Chemica Scripta. Vol, 7, 97 (1975).) On the other hand, compounds represented by formula (III) wherein R⁶ is hydrogen, an alkyl group, a benzyl group or an aryl group, R⁷ and R⁸ are respectively an alkyl group having 2 or more carbon atoms, a benzyl group, an aryl group or unsubstituted or substituted 2-hydroxyethyl group, or R⁷ and R⁸ form a heterocyclic ring together with a nitrogen atom are novel. Examples of an alkyl group, a benzyl group, an aryl group and substituted 2-hydroxyethyl group are the same as those mentioned in the explanation of formula (II).

Examples of novel ferrocene derivatives represented by formula (III) are as follows:

N-[(R)-1-ferrocenylethyl)-N-methyl-2-ethanolamine,

N-[(R)-1-ferrocenylethyl]-(S)-prolinol,

N-[(S)-1-ferrocenylethyl]-(S)-prolinol,

N-[(R)-1-ferrocenylethyl]-(1S,2R)-ephedrine,

N-[(S)-1-ferrocenylethyl]-(1S,2R)-ephedrine,

N-[(R)-1-ferrocenylethyl]-(1S,2R)-norephedrine,

N-(ferrocenylmethyl)-(1S,2R)-ephedrine,

N-[(R)-1-ferrocenylethyl]-N-t-butyl-(S)-2-phenylethanolamine,

N-[(S)-1-ferrocenylethyl]-N-t-butyl-(S)-2-phenylethanolamine.

A novel ferrocene derivative represented by formula (III) can be synthesized by the following method:

A ferrocene derivative (III) wherein R⁷ and R⁸ are other than a methyl group can be synthesized by reacting compound (III) wherein R⁷ and R⁸ are methyl which is a known one (see J. Am. Chem. Soc., vol.92, 5389 (1970)) with methyl iodide to obtain a quaternary ammonium salt and reacting this salt with a primary or secondary amine derivative or ammonia (refer to I.Ugi et al., J. Org. Chem., vol.37, 3052 (1972); T. Hayashi et al., Bull. Chem. Soc. Jpn., vol.53, 1138 (1980)).

Reaction with quaternary ammonium salt ##STR10## MeI: 0.5 to 40 equivalents Solvent: ketones such as acetone, methylethylketone, nitriles such as acetonitrile, benzonitrile

Temperature: -30° to 80° C., preferably -10 to 40° C.

Time: 0.1 to 5 hours

Pressure: atmospheric to increased pressure, preferably 1 to 3 atms

Atmosphere: nitrogen or argon

Separation: when a product is in the form of crystal, it is separated by filtration. Otherwise, prior to filtration, ethylether or hexane is added to a reaction product to form crystals of the product.

Reaction with amine or ammonia ##STR11## HNR⁷ R⁸ : 1 to 30 equivalents Solvent: nitriles such as acetonitrile, benzonitrile ethers such as ethylether, tetrahydrofuran

Temperature: 0° to 100° C., preferably 10° to 90° C.

Time: 0.5 to 100 hours

Pressure: atmospheric to increased pressure, preferably 1 to 3 atms

Atmosphere: nitrogen or argon

Separation: recrystallization or column chromatography

(B) Process 2

In accordance with the following scheme, a haloferrocene derivative (II) can be synthesized by applying the method reported in Tetrahedron, 26, 5453 (1970) to a ferrocene derivative represented by formula (III). ##STR12##

A haloferrocene derivative represented by formula (II) wherein R⁷ and R⁸ are other than a methyl group can be synthesized by the method in which a haloferrocene derivative (II) wherein R⁷ and R⁸ are methyl groups is reacted with methyl iodide to form a quaternary ammonium salt followed by reaction with primary or secondary amine with appropriate R⁷ and R⁸ . (Refer to I.Ugi et al., J. Org. Chem., vol.37, 3052 (1972); T. Hayashi et al., Bull. Chem. Soc. Jpn., vol.53, 1138 (1980).)

Since a number of thus obtaining haloferrocene derivatives are crystallized, a small amount of diastereomers (see J.Am.Chem.Soc., vol.92, 5389(1970)) contained in the product can be removed by recrystallization. Therefore, optically pure ferrocene derivatives (II) and (I) can be obtained.

The compound of the present invention represented by formula (I) can be obtained by lithiation reaction of iodide of haloferrocene derivative (II) which is represented by formula (IV) with n-butyllithium and reaction of the resulting lithiated product with a ketone or aldehyde represented by formula (V) as shown below: ##STR13##

In addition to n-butyl lithium, sec-butyl lithium, t-butyl lithium, methyl lithium and phenyl lithium can be used for lithiation as an organic lithium compound. An amount of the organic lithium compound used in the above reaction ranges from 0.1 to 2.0 equivalents, preferably 0.7 to 1.5 equivalents to ferrocene iodide (IV). It is preferred to use 5 to 30% organic lithium compound solution in hexane or ether. The lithiation reaction is suitably carried out in the presence of a solvent, for example ethers such as ethylether, tetrahydrofuran, straight chain hydrocarbons such as pentane, hexane, heptane, aromatic hydrocarbons such as benzene, toluene, xylene, dichlorobenzene and a mixture of two or more of the above solvents under the following conditions:

Temperature: -30° to 50° C., preferably -10° to 30° C.

Time: 0.1 to 5 hours

Pressure: atmospheric to increased pressure, preferably 1 to 3 atms

Atmosphere: nitrogen or argon

The reaction of the lithiated product with the ketone or aldehyde (V) is preferably conducted by addition of a ketone or aldehyde (V) in ether to the reaction mixture. An amount of the ketone or aldehyde (V) used in this reaction ranges from 0.1 to 2.0 equivalents, preferably 0.7 to 1.5 equivalents to ferrocene iodide (IV) used in the lithiation. This reaction is suitably carried out under the following conditions:

Temperature: -40° to 70° C., preferably -20° to 40° C.

Time: 1 to 3 hours

Pressure: atmospheric to increased pressure, preferably 1 to 3 atms

Atmosphere: nitrogen or argon

The reaction is stopped by addition of an aqueous phosphoric acid solution to the reaction mixture and an aqueous layer is made alkaline. Then the mixture is subjected to extraction with ether and column chromatography to obtain the objective compound represented by formula (I). When compound (V) is an aldehyde, two types of diastereomers are produced by the reaction since a new asymmetric center is generated in the reaction. It is possible to separate these diastereomers from each other by means of chromatography. Since one of the diastereomers has the stable structure, it can also be isolated by subjecting the diastereomers to acid treatment to fully isomerize the other diastereomer (see J.Am.Chem.Soc., vol.95, 482(1973)).

The ketone and aldehyde (V) used in the above reaction are commercially available.

Optically active ferrocene derivatives of the present invention can be a useful ligand to metals with Lewis acidity and therefore, it is possible to provide a catalyst exhibiting good enantioselectivity for asymmetric induction using metals with Lewis acidity such as zinc, boron, aluminum, titanium, cerium and nickel.

Further, according to the present invention, chiral ferrocene derivatives having a wide range of substituents are provided and these derivatives can be applied to various asymmetric syntheses. Furthermore, catalysts for asymmetric synthesis applied to heterogeneous system and polymer gel for optical resolution are expected to be provided by use of the chiral ferrocene derivatives of the present invention. ( See F.S.Arimoto et al., J.Am.Chem.Soc., Vol.77, 6295(1955); Y.Sasaki et al., J.Polym.Sci., Polym.Chem.Ed., Vol.11, 1213(1973).)

The present invention will now be illustrated on the basis of the following examples but the scope of the present invention is not limited to these examples.

EXAMPLE 1

20.0g (77.8 mmol) of (R)-N,N-dimethyl-1-ferrocenyl-ethylamine was added under argon atmosphere to a glass vessel (atmospheric pressure use only) with an agitator and dissolved in acetone 37 ml. After cooling with ice water, methyl iodide 21 ml (337 mmol) was added to the vessel and reacted for 15 minutes under cooling with ice water. After reaction, ethylether 160 ml was added to the vessel and crystals were deposited. The crystals were collected by filtration to obtain (R)-N,N,N-trimethyl-1-ferrocenylethylammonium iodide 31.0 g (77.8 mmol)(yield: 100%).

Then, to the resulting quaternary ammonium salt 31.0 g (77.8 mmol), (1S,2R)-norephedrine 58.8 g (388 mmol) and acetonitrile 370 ml were added and reacted at room temperature. After 48 hours, ethylether was added to the reaction mixture and washed with water. The resulting ether solution was dried over anhydrous sodium sulfate and evaporated. The residue was recrystallized from ethyl acetate to obtain N-[(R)-1-ferrocenylethyl-(1S,2R)-norephedrine 25.4 g (70.0 mmol)(yield: 90%).

[α]_(D) ²³ -65.7° (C 0.530, AcOEt)

Melting point: 147° C.

60MHz ¹ H NMR (δ,CDCl₃); 0.82(3H,d,J=6Hz), 1.40 (3H,d, J=6Hz), 2.55(2H,br,s), 2.85-3.35(1H,m), 3.60(1H,q,J=7Hz), 3.95-4.25(m,9H), 4.70(1H,d,J=4Hz), 7.25(5H,s).

IR(KBr) 3450, 3100, 2998, 2890, 1600, 1105, 995, 905, 830, 810, 702 cm⁻¹.

EXAMPLES 2-4

The procedures of Example 1 were repeated except that N,N-dimethyl-1-ferrocenylethylamines possessing configuration shown in Table 2 were used and amines shown in Table 2 were used in place of norephedrine to obtain ferrocene derivatives listed in Table 2. When the product was liquid, purification was carried out by means of alumina column chromatography. The results were shown in Table 2.

                                      TABLE 2                                      __________________________________________________________________________     Example                                                                             Configuration*                                                                         NR.sup.2 R.sup.3                                                                     Product            Yield (%)                                                                            Specific rotation                                                                       m.p.                      __________________________________________________________________________     2    S       (1S,2R)-nor ephedrine                                                                 ##STR14##         89    [α].sub.D.sup.20                                                         +17.6° (C 0.60,                                                                  97° C.             3    R       (1S,2R)- ephedrine                                                                    ##STR15##         95    [α].sub.D.sup.20                                                         -50.2° (C 1.14,                                                                  oilH)                     4    S       (S)-prolinol                                                                          ##STR16##         93    [α].sub.D.sup.20                                                         +45.1° (C 1.01,                                                                  oilH)                     __________________________________________________________________________      *Configuration of N,Ndimethyl-1-ferrocenylethylamine                     

Spectrum data

Example 2 ##STR17##

60MHz ¹ H NMR (δ,CDCl₃); 0.80(3H,d,J=7Hz), 1.42 (3H,d,J=7Hz),2.20(2H,br,s), 2.80-3.35(1H,m), 3.78 (1H,q,J=7Hz), 4.18(9H,s), 4.70(1H,d,J=4Hz). 7.40(5H,s).

IR(KBr) 3350, 3100, 2995, 1600, 1450, 1105, 1000, 819, 745, 710 cm⁻¹.

Example 3 ##STR18##

60MHz ¹ H NMR (δ,CDCl₃); 0.70(3H,d,J=7Hz), 1.43 (3H,d,J=7Hz),2.01(3H,s), 2.55-3.00(1H,m), 3.21(1H,br,s), 3.80-4.35(10H,m), 4.65(1H,d,J=4Hz), 7.20(5H,s).

IR(neat) 3400, 3100, 2980, 1600, 1450, 1105, 1000, 820, 700 cm⁻¹.

EXAMPLE 4 ##STR19##

60MHz ¹ H NMR (δ,CDCl₃); 1.45 (3H,d,J=7Hz), 1.50-2.10(4H,m), 2.30-2.70(3H,m), 2.75-3.40(3H,m), 3.60-3.75(1H,m), 4.20(9H,s).

IR(neat) 3400, 3100, 2980, 2870, 1400, 1105, 1000 cm⁻¹.

EXAMPLE 5

2.66g (10.3 mmol) of (R)-N,N-dimethyl-1-ferrocenylethylamine was added under argon atmosphere to a 100 ml glass vessel (atmospheric pressure use only) with an agitator and dissolved in ether 25 ml. After cooling with ice water, secondary butyl lithium in cyclohexane 12.4 ml (0.94M, 11.7 mmol) was added dropwise to the vessel and reacted for 1 hour under cooling with ice water. Then the reaction mixture was cooled in a dry ice-acetone bath and iodine (3.00 g, 11.7 mmol) in tetrahydrofuran 25 ml was added dropwise. After 1 hour under cooling, water was added to the vessel to stop the reaction and the aqueous layer was made alkaline. The resulting solution was subjected to extraction with ether and the organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was purified by alumina column chromatography to obtain (R)-N,N-dimethyl-1-[(S)-2-iodoferrocenyl]ethylamine 3.12 g (yiled: 79%). This was recrystallized from acetonitrile. ##STR20##

[α]_(D) ²² =-9.32° (C 1.01, EtOH).

m.p. 78°-79° C.

60 MHz ¹ H NMR (δ,CDCl₃); 1.50(3H,d,J=8.OHz), 2.15(6H,s), 3.15(1H,q,J=7.5Hz), 4.13(7H,s), 4.40-4.60(1H,m).

IR(KBr) 3100, 2970, 2940, 2802, 2760, 1100, 1000cm⁻¹.

EXAMPLES 6-10

The procedures Of Example 5 were repeated excepting that solvents and halogenation agents listed in Table 3 were used. The results were shown in Table 3 below.

                  TABLE 3                                                          ______________________________________                                         Example Solvent    Halogenation agent                                                                            Yield (%)                                    ______________________________________                                         6       ether      Br.sub.2       33                                           7       ether      NBS.sup.1)     10                                           8       ether-THF  NBS.sup.1)     52                                           9       ether      I.sub.2        63                                           10      ether-THF  NIS.sup.2)     53                                           ______________________________________                                          .sup.1) NBS: Nbromosuccinimide                                                 .sup.2) NIS: Niodosuccinimide                                            

EXAMPLES 11-14

The procedures of Example 5 were repeated except that starting materials listed in Table 4 were used in place of (R)-N,N-dimethyl-1-ferrocenylethylamine, 24.8 ml of secondary butyl lithium in cyclohexane was used and ethyl acetate was used as the recrystallization solvent. The results were listed in Table 4.

                                      TABLE 4                                      __________________________________________________________________________     Exam-                                         Yield        m.p.                ple Starting material    Product              (%) Specific                                                                                (°C.)        __________________________________________________________________________     11                                                                                  ##STR21##                                                                                           ##STR22##           55  [α].sub.D.sup.20                                                         -37.1° (c 1.05,                                                         EtOH)     90                 12                                                                                  ##STR23##                                                                                           ##STR24##           46  [α].sub.D.sup.22                                                         -21.9° (c 0.42,                                                         AcOEt)   157                 13                                                                                  ##STR25##                                                                                           ##STR26##           52  [α].sub.D.sup.20                                                         +30.3° (c 0.578,                                                        AcOEt)   112                 14                                                                                  ##STR27##                                                                                           ##STR28##           50  [α].sub.D.sup.20                                                         -20.9° (c 1.246,                                                        EtOH)    oil                 __________________________________________________________________________

EXAMPLE 11

60 MHz ¹ H NMR (δ,CDCl₃); 1.40(3H,d,J=7.0Hz), 2.10(3H,s), 2.53(2H,t,J=5.0Hz), 2.70(1H,s), 3.50(2H,t,J=5.0Hz), 3.90 (1H,q,J=7.0Hz), 4.11(5H,s), 4.16-4.31(2H,m), 4.42-4.61(1H,m).

IR(KBr) 3450, 3098, 2950, 2890, 1105, 1000cm⁻¹.

EXAMPLE 12

400 MHz ¹ H NMR (δ,CDCl₃); 1.44(3H,br), 1.58(2H,br), 1.72-1.88(2H,m), 2.43(1H,br), 2.52(1H,br), 2.80(1H,s), 3.01(1H,br), 3.29(1H,br), 3.7l(1H,br), 3.98(1H,q,J=8.0Hz), 4.12(5H,s), 4.17-4.47(4H,m).

IR(KBr) 3450, 3098, 2960, 1102, 1000cm⁻¹.

EXAMPLE 13

400 MHz ¹ H NMR (δ,CDCl₃); 1.57(3H,br), 1.50-1.78(4H,m), 2.60(2H,br), 2.90-3.18(3H,br), 3.98(1H,br), 4.12(5H,s), 4.15-4.30(3H,m).

IR(KBr) 3450, 3100, 2970, 1105, 1000cm⁻¹.

EXAMPLE 14

60 MHz ¹ H NMR (δ,CDCl₃); 0.98(3H,d,J=7.0Hz), 1.37 (3H,d,J=7.0Hz), 2.12(3H,s), 2.60-3.12(1H,m), 3.57(1H,s), 4.12(5H,s), 4.23-4.27(3H,m), 4.67-4.72(1H,m), 7.30(5H,s).

IR(neat) 3450, 3100, 3070, 2995, 1608, 1108, 1000, 940, 820, 755, 700 cm⁻¹.

EXAMPLE 15

3.83g (10.0 mmol) of (R)-N,N-dimethyl-1-[(S)-2-iodoferrocenyl]ethylamine was added under argon atmosphere to a glass vessel (atmospheric pressure use only) with an agitator and dissolved in acetone 20 ml. Methyl iodide 2.86 ml (46 mmol) was added to the vessel and reacted for 10 minutes at room temperature. After reaction, ethylether 100 ml was added to the vessel and crystals were precipitaed. The crystals were collected by filtration to obtain the quaternary ammonium salt 5.25 9 (10.0 mmol).

Then the resulting quaternary ammonium salt was dissolved in acetonitrile 130 ml. Diethylamine 26 ml (250 mmol) was added to this solution and the reaction mixture was stirred at 30° C. for 48 hours. Ethylether was added to the reaction mixture and washed with water. The resulting ether solution was dried over anhydrous sodium sulfate and evaporated. The residue was recrystallized from ethyl alcohol to obtain (R)-N,N-diethyl-1-[(S)-2-i odoferrocenyl]ethylamine 3.70 g (9.0 mmol)(yield: 90%). ##STR29##

[α]_(D) ²⁷ -58.6° (C 0.596, EtOH),

Melting point: 49° C.

90MHz ¹ H NMR (δ,CDCl₃); 0.98(6H,t,J=7.2Hz), 1.39 (3H,d,J=6.6Hz), 2.39 (2H,q,J=6.9Hz), 2.42 (2H,q,J=6.9Hz), 3.90 (1H, q,J=6.6Hz), 4.09 (5H,s), 4.15-4.21(2H,m), 4.38-4.44(1H,m).

IR (KBr) 3100, 2980, 2820, 1104, 1001, 820cm⁻¹.

EXAMPLES 16-17

In accordance with the procedures of Example 15 except that amines listed in Table 5 were used instead of diethylamine, the products shown in Table 5 were obtained.

Product of Example 16

90MHz ¹ H NMR (δ,CDCl₃); 1.16-1.50(6H,m), 1.50(3H,d, J=6.3Hz), 2.36 (3H,t,J=5.1Hz), 3.70 (1H,q,J=7.2Hz), 4.10 (5H,s), 4.16-4.25(2H,m), 4.39-4.49(1H,m).

IR (KBr) 3100, 2950, 2860, 2805, 2760, 1108, 1002, 820 cm⁻¹.

Product of Example 17

90MHz ¹ H NMR (δ,CDCl₃); 0.96(6H,d,J=6.0Hz), 1.06 (6H,d,J=6.0Hz), 1.49 (3H,d,J=6.3Hz), 2.89-3.37(2H,m), 4.03(1H,q,J=6.6Hz), 4.06(5H,s), 4.10-4.28(2H,m), 4.36-4.45(1H,m).

IR (KBr) 3105, 2995, 2898, 1365, 1195, 1109, 1002, 820 cm⁻¹.

                                      TABLE 5                                      __________________________________________________________________________     Example                                                                             Amine  Product            Yield (%)                                                                            Specific rotation                                                                       m.p. (°C.)                __________________________________________________________________________     16                                                                                   ##STR30##                                                                             ##STR31##         90    [α].sub.D.sup.26 -21.9°                                           C 0.960, EtOH)                                                                          67                               17   HN(i-Pr).sub.2                                                                         ##STR32##         80    [α].sub.D.sup.26 -77.6°                                           C 1.08, EtOH)                                                                           58-60                            __________________________________________________________________________

EXAMPLE 18

2.12g (5.0 mmol) of (R)-1-[(S)-2-iodoferrocenyl]-1-(1-piperidino)ethane obtained in Example 16 was added under argon atmosphere to a glass vessel (atmospheric pressure use only) with an agitator and dissolved in ethylether 12 ml. After cooling with ice water, n-butyl lithium in hexane 3.13 ml (1.60 M, 5.0 mmol) was added dropwise to the vessel and reacted for 5 minutes under cooling with ice water. Then, benzophenone 911 mg (5.0 mmol) in ether 15 ml was added to the reaction mixture and stirred at room temperature for 1 hour. 8% aqueous phosphoric acid solution was added to the mixture to stop the reaction. The resulting acid solution was washed with ethylether and treated with a conc. aqueous alkaline solution to make it alkaline. Thus obtained alkaline solution was subjected to extraction with ethylether and the ethylether solution was dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by alumina column chromatography (hexane:AcOEt) to obtain (R)-1-[(S)-2-diphenylhydroxymethyl-ferrocenyl]- 1-(1-piperidino)ethane 1.80 g (3.75 mmol, yield: 75%). ##STR33##

[α]_(D) ²¹ -209.9° (C 0.490, EtOH).

Melting point: 62°-69° C.

90MHz ¹ H NMR (δ,CDCl₃); 0.29-1.70 (6H,m), 1.24 (3H,d,J=6.3Hz), 2.25 (4H,t,J=5.7Hz), 3.80 (5H,s), 3 89-4.01(1H,m), 4.03-4.20(1H,m), 4.20-4.37(1H,m), 4.40(1H,q,J=6.9Hz), 6.98-7.45(8H,m), 7.50-7.75(2H,m), 8.72(1H,s,OH).

IR (KBr) 3460, 3100, 3070, 2950, 2840, 1600, 1444, 1104, 1002, 820, 762, 753, 703cm⁻¹.

EXAMPLES 19-23

According to the procedures of Example 18 except that ferrocene derivatives listed in Table 6 were used in place of (R)-1-[(S)-2-iodoferrocenyl]-1-(1-piperidino)ethane and ketones listed in Table 6 were used in place of benzophenone, the products shown in Table 6 were obtained.

                                      TABLE 6                                      __________________________________________________________________________                                                 Yield                                                                               Specific                      Example                                                                             Starting material     Product          (%)  rotation                                                                               m.p.                  __________________________________________________________________________                                                              (°C.)          19                                                                                   ##STR34##                                                                                            ##STR35##       40   [α].sub.D.sup.27                                                         +50.8° (c 0.634,                                                        EtOH)   60-61                 20                                                                                   ##STR36##                                                                                            ##STR37##       50   [α].sub.D.sup.27                                                         -17.3° (c 0.550,                                                        EtOH)   108                   21                                                                                   ##STR38##                                                                                            ##STR39##       65   [α].sub.D.sup.26                                                         -229.5° (c 0.346,                                                       EtOH)   48-50                 22                                                                                   ##STR40##                                                                                            ##STR41##       43   [α].sub.D.sup.26                                                         -190.6° (C 0.770,                                                       EtOH)   90-93                       ##STR42##                                                                23                                                                                   ##STR43##                                                                                            ##STR44##       52   [α].sub.D.sup.25                                                         -192.0° (C 0.762,                                                       EtOH)   50-53                 __________________________________________________________________________

Product of Example 19

90MHz ¹ H NMR (δ,CDCl₃); 0.37(3H,d,J=6.6Hz), 0.85 (3H,d,J=6.3Hz), 1.29 (6H,d,J=6.6Hz), 1.45 (3H,d,J=6.6Hz), 1.60-1.97 (1H,m), 2.10 (6H,s), 2.30-2.68(1H,m), 3.78-3.95 (1H,m), 4.09(5H,s), 4.11-4.23(3H,m), 7.69(1H,s,-OH).

IR (KBr) 3420, 3100, 2998, 2898, 2800, 1108, 1004, 828, 820cm⁻¹.

Product of Example 20

90MHz ¹ H NMR (δ,CDCl₃); 1.21(3H,d,J=6.3Hz), 1.30-2.42 (10H,m), 2.09(6H,s), 3.90-4.09(3H,m), 4.12(5H,s), 4.29 (1H,q, J=6.3Hz). 7.18(1H,s,--OH).

IR (KBr) 3450, 3100, 2950, 2800, 1105, 822cm⁻¹.

Product of Example 21

90MHz ¹ H NMR (δ,CDCl₃); 0.63(6H,t,J=7.2Hz), 1.20 (3H,d, J=6.0Hz), 1.89-2.58(4H,m), 3.78 (5H,s), 3.89-4.03(1H,m), 4.07-4.20(1H,m), 4.20-4.31(1H,m), 4.65(1H,q,J=6.9Hz), 6.98-7 48(8H,m), 7.53-7.76(2H,m) 8.70(1H,s,--OH).

IR (KBr) 3450, 3100, 3060, 2995, 2860, 1598, 1109, 1003, 820, 755, 702cm⁻¹.

Product of Example 22

90MHz ¹ H NMR (δ,CDCl₃); 1.32(3H,d,J=6.0Hz), 1.35-1.95(6H, m), 2.64(4H,t,J=5.4Hz), 3.20-3.39(1H,m), 3.50(5H,s), 3.70-3.90(1H,m), 3.90-4.02(1H,m), 4.02-4.l8(1H,m), 4.20-4.60(2H, m), 7.06-7.50(4H,m), 7.60-7.83(1H,m), 7.89-8.09(1H,m).

IR (KBr) 3460, 3100, 3150, 2950, 2830, 1108, 1001, 820, 760, 747cm⁻¹.

Product of Example 23

90MHz ¹ H NMR (δ,CDCl₃); 0.69(6H,d,J=6.0Hz), 1.09(6H,d, J=6.0Hz), 1.38(3H,d,J=6.3Hz), 2.85-3.22(2H,m), 3.70(5H,s), 3.90-4.10(1H,m), 4.10-4.Z3(1H,m), 4.23-4.37(1H,m). 4.82 (1,q,J=6.9Hz), 6.98-7.47(8H,m), 7.60-7.83(2H,m), 8.45(1H,s,--OH).

IR (KBr) 3450, 3100, 3070, 2990, 2890, 1600, 1105, 1000, 819, 750, 700cm⁻¹.

EXAMPLES 24-26

The procedures of Example 18 were repeated except that ferrocene derivatives listed in Table 7 were used in place of (R)-1-[(S)-2-iodoferrocenyl]-1-(1-piperidino)ethane and aldehydes listed in Table 7 were used in place of benzophenone as a carbonyl compound. The products of these examples contained two diastereomers. These diastereomers were separated by means of chromatography using alumina or silica gel, and physical properties of each diastereomer were measured and shown in Table 7.

                                      TABLE 7                                      __________________________________________________________________________                                                              m.p.                                                                           (°C.)          Ex-                                                      pro-                                                                              pro-               am-                                  Yield                                                                              Specific rotation (C,                                                                          ductent)                                                                          duct               ple                                                                               Starting material                                                                               Product          (%) product 1                                                                              product                                                                                1  2                  __________________________________________________________________________     24                                                                                 ##STR45##                                                                                       ##STR46##       65  [α].sub.D.sup.27                                                         -120.6° (C 1.04,                                                                [α].sub.D.sup.24                                                         -92.0° (C 0.766,                                                        EtOH)   oil                                                                               oil                25                                                                                 ##STR47##                                                                                       ##STR48##       73  [α].sub.D.sup.26                                                         -44.2° (C 0.606,                                                                [α].sub.D.sup.26                                                         +130.2° (C 0.765,                                                       EtOH)   121-124                                                                           91                 26                                                                                 ##STR49##                                                                                       ##STR50##       60  [α].sub.D.sup.28                                                         -30.8° (C 0.120,                                                                [α].sub.D.sup.28                                                         +131.2° (C 0.128,                                                       EtOH)   oil                                                                               oil                __________________________________________________________________________

Example 24

Product 1

90MHz ¹ H NMR (δ,CDCl₃); 1.36(3H,d,J=6.6Hz), 2.22(6H,s), 3.38-3.58(1H,m), 3.80-4.40(3H,m), 4.03(5H,s), 5.94(1H,s), 7.12-7.68(5H,m), 7.70-8.02(1H,s,OH).

IR (neat) 3102, 3049, 2998, 2849, 2800, 1605, 1105, 1000, 819, 738, 700cm⁻¹.

Product 2

90MHz ¹ H NMR (δ,CDCl₃); 1.23(3H,d,J=6.0Hz), 2.19(6H,s), 3.80(5H,s), 3.90-4.35(4H,m), 5.47(1H,s), 6.00-6.70(1H,--OH), 7.09-7.68(5H,m).

IR (neat) 3370, 3100, 3040, 2998, 2798, 1600, 1104, 1000, 818, 719, 700cm⁻¹.

Example 25

Product 1

90MHz ¹ H NMR (δ,CDCl₃); 0.94(9H,s), 1.29(3H, d,J=6.6Hz), 2.07(6H,s), 2.62(1H,--OH), 3.80(1H,q,J=7.5Hz), 3.97-4.25 (3H,m), 4.16(5H,s), 4.25-4.35(1H,m).

IR (KBr) 3480, 3105, 2999, 2970, 2840, 2800, 1106, 1002, 818cm⁻¹.

Product 2

90MHz ¹ H NMR (δ,CDCl₃); 1.18(9H,s), 1.29(3H,d,J=6.0Hz), 2.15(6H,s), 4.00(5H,s), 4.05-4.18(3H,m), 4.19-4.34(1H,m), 4.52(1H,s), 7.60(1H,--OH).

IR (KBr) 3450, 3102, 3000, 2960, 2850, 2800, 1108, 1005, 820cm⁻¹.

Example 26

Product 1

90MHz ¹ H NMR (δ, CDCl₃); 0.99(9H,s), 1.27(3H, d,J=5.4Hz), 1.18-1.55(6H,m), 2.20-2.60(4H,m), 3.79(1H,q,J=7.2Hz), 3.97-4.37(4H,m), 4.11 (5H,s).

IR (neat) 3100, 3000, 2950, 2820, 1105, 1000, 820 cm⁻¹.

Product 2

90MHz ¹ H NMR (δ,CDCl₃); 1.20(9H,s), 1.33(3H,d,J=6.0Hz), 1.29-1.56(6H,m), 2.32-2.57(4H,m), 4.00(5H,s), 4.03-4.20 (3H,m), 4.20-4.37(1H,m), 4.50(1H,s).

IR (neat) 3250, 3105, 3000, 2960, 2840, 1112, 1009, 822 cm⁻¹.

EXAMPLES 27-28

The procedures of Example 18 were repeated except that (R)-N,N-dimethyl-1-[(S)-2-iodoferrocenyl]ethylamine was used in place of (R)-1-[(S)-2-iodoferrocenyl]-1-(1-piperidino)ethane and aldehydes listed in Table 8 were used in place of benzophenone as a carbonyl compound. Products of these examples contained two diastereomers and these diastereomers were separated by means of chromatography using alumina or silica gel. Physical properties of each diastereomer separated were measured and shown in Table 8.

Example 27

Product 1

90MHz ¹ H NMR (δ,CDCl₃); 1.30(3H,d,J=6.6Hz), 2 07(6H,s), 2.24(3H,s), 2.43(6H,s), 3.78-3.95(1H,m), 3.95-4.30(3H,m), 4.15(5H,s), 6.06(1H,s), 6.77(2H,s).

IR (KBr) 3450, 3100, 3000, 2980, 2840, 2800, 1610, 1464, 1319, 1107, 1000, 950, 812, 785, 737, 700 cm⁻¹.

Product 2

90MHz ¹ H NMR (δ,CDCl₃); 1.38(3H,d,J=6.8Hz), 2.21(6H,s), 2.27(3H,s), 2.38(6H,s), 3.57-3.75(1H,m), 3.93(1H,m, J=2.6Hz), 4.03(5H,s), 4.10-4.23(1H,m), 4.20(1H,q,J=6.8Hz), 6.53(1H,s), 6.82(1H,s), 8.28(1H,OH).

IR (KBr) 3450, 3100, 2999, 2950, 2850, 2800, 1610, 1460, 1370, 1182, 1109, 1072, 1043, 1003, 950, 938, 818, 770, 735, 680cm⁻¹.

Example 28

Product 1

90MHz ¹ H NMR (δ,CDCl₃); 1.35(3H,d,J=6.8Hz), 2.27(6H,s), 3.52-3.65(1H,m), 3.87 3.99(1H,m), 3.97(5H,s), 4.15-4.24 (1H,m), 4.47(1H,q,J=6.8Hz), 6.05(1H,OH), 7.17(1H,s), 7.30-7.60(4H,m), 7.88-8.10(2H,m), 8.10(1H,s), 8.85-9.10(2H,m).

IR (KBr) 3440, 3100, 3050, 2970, 2910, 2815, 2775, 1620, 1520, 1365, 1260, 1104, 1040, 1000, 880, 732cm⁻¹.

Product 2

90MHz ¹ H NMR (δ,CDCl₃); 1.47(3H,d,J=6.8Hz), 2.34(6H,s), 3.30-3.42(1H,m), 3.83(5H,s), 4.04-4.16(1H,m), 4.18-4.30 (1H,m), 4.51(1H,q,J=6.8Hz), 7.25-7.53(4H,m), 7.55(1H,s), 7.89-8.10(2H,m), 8.44(1H,s), 8.60-8.90(2H,m).

IR (KBr) 3440, 3100, 2990 2930, 2785, 1600, 1510, 1350, 1265, 1108, 1035, 1005, 880, 730cm⁻¹.

EXAMPLES 29-30

The procedures of Example 18 were repeated except that (R)-N,N-dimethyl 1-[S)-2-iodoferrocenyl]ethylamine was used in place of (R)-1-[(S)-2-iodoferrocenyl]-1-(1-piperidino)ethane, aldehydes listed in Table 9 were used in place of benzophenone as a carbonyl compound, and reactions were stopped by addition of 8% aqueous phosphoric acid solution and the acid solution was allowed to stand for 0.1 to 4 hours at room temperature. Products were completely isomerized to diastereomers listed in Table 9 by this treatment. Physical properties of the diastereomers were shown in Table 9.

Example 29

90MHz ¹ H NMR (δ,CDCl₃); 1.35(3H, d,J=6Hz), 2.20(6H,s), 3.78(6H,s), 3.70-4.00(2H,m), 3.93(5H,s), 4.02-4.20 (1H,m), 4.30(1H,q,J=7.0Hz), 6.58(1H,s), 6.68(2H,d,J=3.3Hz), 7.23(1H,d-d,J=8.4Hz,J=7.0Hz).

IR (KBr) 3450, 3100, 2998, 2950, 2848, 2800, 1595, 1475, 1245, 1180, 1100, 1004, 920, 808, 730 cm⁻¹.

Example 30

90MHz ¹ H NMR (δ,CDCl₃); 1.30(3H,d,J=6.8Hz), 2.19(6H,s), 3.58-3.73(1H,m), 3.92(1H,t,J=2.6Hz), 4.03(5H,s), 4.04-4.22 (4H,m), 4.27(5H,s), 4.28-4.45(2H,m), 5.67(1H,s), 7.30(1H,OH).

IR (KBr) 3450, 3100, 2995, 2950, 2840, 2800, 1500, 1460, 1368, 1290, 1042, 1005, 1000, 935, 815, 770, 740cm⁻¹.

                                      TABLE 8                                      __________________________________________________________________________     Example                                                                             Aldehyde       Product        Yield (%)                                                                            Specific rotation                                                                      m.p. (°C.)             __________________________________________________________________________     27                                                                                   ##STR51##                                                                                     ##STR52##     70    Product 1 [α].sub.D.sup.22                                               +109.6° (C 0.356, EtOH)                                                 Product 2 [α].sub.D.sup.20                                               -135.2° (C 0.398,                                                               136-139  54-57                28                                                                                   ##STR53##                                                                                     ##STR54##     58    Product 1 [α].sub.D.sup.20                                               -51.3° (C 0.372, EtOH)                                                  Product 2 [α].sub.D.sup.20                                               +64.8° (C 0.276,                                                                 60-62  98-103                __________________________________________________________________________

                                      TABLE 9                                      __________________________________________________________________________     Example                                                                             Aldehyde    Product        Yield (%)                                                                            Specific rotation                                                                      m.p. (°C.)                __________________________________________________________________________     29                                                                                   ##STR55##                                                                                  ##STR56##     50    [α].sub.D -51.7° (C                                               0.704, EtOH)                                                                           45-47                            30                                                                                   ##STR57##                                                                                  ##STR58##     45    [α].sub.D +45.2° (C                                               0.354, EtOH)                                                                           65-68                            __________________________________________________________________________ 

What we claim is:
 1. An optically active haloferrocene derivative represented by the following formula (II): ##STR59## wherein R⁶ represents an alkyl group, R⁷ and R⁸ respectively represent hydrogen, an alkyl group, a benzyl group, an aryl group, 2-hydroxyethyl group or 2-hydroxyethyl group substituted at a carbon atom with at least one member selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, phenyl and p-tolyl, or R⁷ and R⁸, together with a nitrogen atom, form a heterocyclic ring selected from the group consisting of pyrrolidyl, (S)-2-hydroxymethylpyrrolidyl, (R)-2-hydroxymethylpyrrolidyl, piperidyl, morpholyl, (S)-2-(diphenylhydroxymethyl)pyrrolidyl, (S)-2-[(S)-phenylhydroxymethyl]pyrrolidyl and (S)-2-[(R)-phenylhydroxymethyl]pyrrolidyl, X¹ and X² represent hydrogen or halogen atoms, and one of X¹ and X² is hydrogen and the other is halogen atom.
 2. An optically active ferrocene derivative represented by the formula (III): ##STR60## wherein R⁶ represents hydrogen or an alkyl group, R⁷ represents hydrogen or an alkyl group and R⁸ represents 2-hydroxyethyl group or 2-hydroxyethyl group substituted at a carbon atom with at least one member selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, phenyl and p-tolyl, or R⁷ and R⁸, together with a nitrogen atom, form a heterocyclic ring selected from the group consisting of pyrrolidyl, (S)-2-hydroxymethylpyrrolidyl, (R)-2-hydroxymethylpyrrolidyl, piperidyl, morpholyl, (S)-2-(diphenylhydroxymethyl)pyrrolidyl, (S)-2-[(S)-phenylhydroxymethyl]pyrrolidyl and (S)-2-[(R)-phenylhydroxymethyl]pyrrolidyl.
 3. An optically active ferrocene derivative of claim 1 wherein R⁶ represents an alkyl group.
 4. An optically active haloferrocene derivative of claim 1 wherein X¹ or X² represents an iodo atom.
 5. An optically active haloferrocene derivative of claim 1 wherein X¹ or X² represents a bromo atom.
 6. An optically active haloferrocene derivative of claim 1 wherein R⁸ represents an alkyl group having 1 to 6 carbon atoms.
 7. An optically active haloferrocene derivative of claim 1 wherein R⁷ and R⁸ respectively represent an alkyl group having 1 to 6 carbon atoms.
 8. An optically active haloferrocene derivative of claim 1 wherein R⁷ and R⁸, together with a nitrogen atom, form a heterocyclic ring selected from the group consisting of pyrrolidyl, (S)-2-hydroxymethylpyrrolidyl, (R)-2-hydroxymethylpyrrolidyl, piperidyl, morpholyl, (S)2-(diphenylhydroxymethyl)pyrrolidyl, (S)-2-[(S)-phenylhydroxymethyl]pyrrolidyl and (S)-2-[(R)-phenylhydroxymethyl]pyrrolidyl.
 9. An optically active haloferrocene derivative of claim 8 wherein the heterocyclic ring is selected from the group consisting of pyrrolidyl, piperidyl and morpholyl.
 10. An optically active ferrocene derivative of claim 3 wherein R⁸ represents an alkyl group having 1 to 6 carbon atoms.
 11. An optically active ferrocene derivative of claim 2 wherein R⁷ represents an alkyl group having 1 to 6 carbon atoms.
 12. An optically active ferrocene derivative of claim 2 wherein R⁸ represents 2-hydroxyethyl group substituted at a carbon atom with at least one member selected from the group consisting of methyl, ethyl, iso-propyl, tert-butyl, phenyl and p-tolyl.
 13. An optically active ferrocene derivative of claim 2 wherein R⁷ and R⁸, together with a nitrogen atom, form a heterocyclic ring selected from the group consisting of pyrrolidyl, (S)-2-hydroxymethylpyrrolidyl, (R)-2-hydroxymethylpyrrolidyl, piperidyl, morpholyl, (S)-2-(diphenylhydroxymethyl)pyrrolidyl, (S)-2-[(S)-phenylhydroxymethyl]pyrrolidyl and (S)-2-[(R)-phenylhydroxymethyl]pyrrolidyl. 